This study will investigate the relation of early developmental insult (EDI) to adult brain disturbance among cases of schizophrenia and schizophrenia spectrum disorder (SSD). The study represents a collaborative effort between epidemiologists and clinical neuroscientists, in which advanced neuroimaging and neuropsychological approaches are brought to bear on a large birth cohort with extensive early developmental exposure data. The proposal study builds upon two unique investigations, the Child Health and Development Study (CHDS) and one of its extensions, the Prenatal Determinants of Schizophrenia (PDS) Study. The CHDS was based on a cohort of 19,044 live births during 1959-1966 in the Oakland Hospital of the Kaiser Foundation Health Plan (KFHP). Using cases already diagnosed in the PDS study, and cases to be diagnosed in the present study, we expect that 100-11O cases and 100-110 matched controls will be assessed for all the proposed adult brain disturbances. Specifically, the applicants aim to: 1) Compare case of SSD with matched controls from the PDS study with respect to adult brain disturbances indicative of early development insult. The applicants hypothesize that associations will be demonstrated between SSD and adult brain disturbances in the following dimensions: neuroanatomical, neurochemical, and neuropsychological; 2) Examine, among cases of SSD, associations between EDI and adult brain disturbances; and 3) For those adult brain disturbances that show a relation to ED! in Aim 2, the applicants will then examine evidence for whether familial liability to SSD contributes to EDI, leading to the above adult brain abnormalities in SSD cases. This study has several notable strengths, which include: extensive prospectively collected data on EDT and prenatal sera for analysis of additional early developmental exposures; research-based diagnoses; good control of bias; a representative sample of control subjects; more refined and extensive brain measures; good statistical power; and the ability to analyze causal pathways. Important implications of this study are to provide evidence of pathogenic mechanisms by which ED! might lead to SSD, lend validation for the neurodevelopment hypothesis of schizophrenia, and elucidate underpinnings of the diverse brain disturbances found in patients with SSD.